Thiol S-methylation in uremia: Erythrocyte enzyme activities and plasma inhibitors

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Abstract
Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs, i.e., 6-mercaptopurine. Thiol methyltransferase (TMT) catalyzes the S-methylation of a variety of aliphatic sulfhydryl compounds. Erythrocyte (RBC) TPMT activity is elevated in the blood of uremic patients on maintenance hemodialysis, 15.83 .+-. 0.90 U/ml RBC (.hivin.x, mean .+-. SEM, SE of mean, n = 41), but in blood from randomly selected nonuremic subjects it was 12.76 .+-. 0.16 U/ml (n = 298, P < 0.001). RBC TPMT activity is not affected by hemodialysis. The plasma of uremic patients reversibly inhibits RBC TPMT activity to a greater extent than normal plasma does and contains higher concentrations of endogenous methyl acceptors than normal plasma. Plasma TPMT inhibitiors are not removed by hemodialysis. There are large individual variations in inhibition of RBC TPMT by plasma from patients with renal failure. Inhibition varied 1-93% in 20 .mu.l of plasma from each of 20 randomly selected uremic patients. There was a positive correlation between the inhibition of TPMT and the content of endogenous methyl acceptors in uremic plasma (r = 0.914, n = 20, P < 0.001), but there was no significant correlation between degree of inhibition and urea N, serum creatinine or hematocrit. The ability of plasma from individual uremic patients to inhibit TPMT correlated with its ability to inhibit 2 other drug-metabolizing methyltransferases in the RBC, catechol-O-methyltransferase and phenol-O-methyltransferase. RBC TMT activity is not altered in patients with uremia. The results of these and other studies of methylconjugation in renal failure focus attention on the accumulation of methyl acceptor substrates in some of these patients and on the possible effects of these methyl acceptors on a variety of methylation reactions.